The Bcl-2 family of proteins, which plays an important role in regulating cell survival and cell death, can be divided into two groups, proapoptotic proteins (Bak and Bak) and anti-apoptotic proteins (Bcl-2, Bcl-xL, Al, Mcl-1, and Bcl-w) (Adams et al. (1998) Science 281:1322-1326; Henson et al. (2006) Clin. Cancer Res. 12(3):845-853). Antiapoptotic family member Mcl-1 was first characterized from a myeloid leukemia cell line (ML-1) induced to differentiate along the monocytic lineage (Kozopas et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:3516-3520; Leuenroth et al. (2000) J. Leukoc. Biol. 68:158-166) and has since been shown to be expressed in a wide variety of tissues and neoplastic cells and to influence the development of numerous malignancies (Thallinger et al. (2004) Clin. Cancer Res. 10:4185-4191).
The role of Mcl-1 in regulating cell fate has made it a target of interest in many studies of apoptosis and hyperproliferative diseases. Many reports have demonstrated the importance of inhibiting Mcl-1 expression to increase apoptosis and regulate neoplastic disease.
U.S. Pat. No. 6,001,992 discloses antisense oligonucleotides for inhibition of expression of anti-apoptotic bcl-2 related proteins, including Mcl-1.
U.S. Pat. No. 6,800,750 discusses Mcl-1 regulatory elements, oligonucleotide primers which hybridize to Mcl-1 and methods of modulating apoptosis of a cell by modulating expression of Mcl-1.
WO 94/29330 discloses Mcl-1 polypeptide and polynucleotide sequences and discusses methods of treating a subject having a cell proliferative disorder.
Several studies have reported use of Mcl-1 antisense oligonucleotides or siRNA to inhibit Mcl-1 expression, increase apoptosis, decrease cell viability and/or decrease tumor weight of normal cells, cancer cell lines or xenograft tumors. Henson et al. ((2006) Clin. Cancer Res. 12(3):845-853) disclose a Mcl-1 antisense oligonucleotide which sensitizes breast cancer cell lines to apoptosis. Selzer et al. ((2002) Mol. Med. 8(12):877-884) disclose inhibition of Mcl-1 expression in melanoma cells using an antisense oligonucleotide targeting Mcl-1 and Skvara et al. ((2005) Anticancer Res. 25(4):2697-2703) show a Mcl-1 antisense oligonucleotide which sensitizes human melanoma cells to ionizing radiation-induced apoptosis. Sieghart et al. ((2006) J. Hepatol. 44(1):151-157) discuss the finding the Mcl-1 is overexpressed in hepatocellular carcinoma cells lines and disclose a Mcl-1 antisense oligonucleotide which decreases protein expression, increases apoptosis, decreases cell survival and sensitizes HCC cells to chemotherapy. Similarly, Song et al. ((2005) Cancer Biol. Ther. 4(3):267-276) show that Mcl-1 is overexpressed in human lung cancer cells and treatment with a Mcl-1 antisense oligonucleotide resulted in an increase in apoptosis. Mcl-1 inhibition also caused sensitization of the lung cancer cells to apoptosis induced by chemotherapeutic agents and radiation.
Aichberger et al. ((2005) Blood 105(8):3303-3011) discuss a Mcl-1 antisense oligonucleotide and siRNA which inhibit expression of Mcl-1 in chronic myeloid leukemia cells and decreased cell viability. Mcl-1 antisense oligonucleotide synergized with the BCR/ABL inhibitor Imatinib to produce growth arrest. Derenne et al. ((2002) Blood 100(1):194-199) and Zhang et al. ((2002) Blood 99(6):1885-1893) discuss use of Mcl-1 antisense oligonucleotide to decrease expression of Mcl-1, decrease cell viability and increase apoptosis of multiple myeloma cells lines and primary cells.
Mcl-1 has also been shown to exhibit increased expression in a variety of hematopoietic cells lines, including B cells, monocytes, macrophages and polymorphonuclear cells, and treatment of these cells with Mcl-1 antisense oligonucleotide reduces target expression and increases apoptosis (Michels et al. (2004) Oncogene 23(28):4818-4827; Sly et al. (2003) J. Immunol. 170(1):430-437; Liu et al. (2001) J. Exp. Med. 194(2):113-126; Moulding et al. (2000) Blood 96(5):1756-1763; and Leuenroth et al. (2000) J Leukoc. Biol. 68:158-166).
Thallinger et al. ((2004) Clin. Cancer Res. 10:4185-4191) disclose an antisense oligonucleotide targeted to Mcl-1 which decreases expression of Mcl-1 in sarcoma xenotransplants and when used in combination with cyclophosphamide, reduces tumor weight and increases tumor cell apoptosis. Thallinger et al. ((2003) J. Invest. Dermatol. 120(6):1081-1086) show a Mcl-1 antisense oligonucleotide administered systemically with or without dacarbazine in a human melanoma SCID mouse xenotransplantation model decreased target protein expression, increased apoptosis and decreased tumor weight.
Given the role of Mcl-1 in a variety of disorders, including hyperproliferative disorders, an efficient method of modulating expression of Mcl-1 is desirable. Antisense technology is an effective means for reducing the expression of one or more specific gene products and is uniquely useful in a number of therapeutic, diagnostic, and research applications. Provided herein are antisense compounds for use in modulation of Mcl-1 expression.